ClinVar Miner

Submissions for variant NM_000304.4(PMP22):c.469C>T (p.Arg157Trp) (rs28936682)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneReviews RCV000193053 SCV000243949 pathogenic Charcot-Marie-Tooth disease and deafness 2014-12-18 no assertion criteria provided literature only
Illumina Clinical Services Laboratory,Illumina RCV000778488 SCV000914750 uncertain significance PMP22-Related Disorders 2017-12-19 criteria provided, single submitter clinical testing The PMP22 c.469C>T (p.Arg157Trp) variant has been reported in two studies and is found in a total of four individuals, including three in a homozygous state and one in a heterozygous state (Parman et al. 1999; Brown et al. 2014). Parman et al. (1999) reported the p.Arg157Trp variant in a homozygous state in three siblings with a clinical diagnosis of Dejerine-Sottas disease, which is a historical name used to describe a severe and early childhood onset type of Charcot-Marie-Tooth disease (CMT). Their unaffected parents were reported to be first cousins and were both found to carry the p.Arg157Trp variant in a heterozygous state. Brown et al. (2014) identified the p.Arg157Trp variant in a heterozygous state in one individual who was referred for testing for hereditary neuropathy with liability to pressure palsies. The p.Arg157Trp variant was absent from 50 controls (Parman et al. 1999). It is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele so the variant is presumed to be rare. Liu et al. (2014) studied the effect of the p.Arg157Trp variant and found an increase in formation of medium-sized aggregates, an increase in intracellular accumulation, a reduction of calnexin colocalization, and a low level of surface expression compared to wild type. Based on the evidence, the p.Arg157Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for PMP22-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000008957 SCV000029169 pathogenic Autosomal recessive Dejerine-Sottas syndrome 1999-04-01 no assertion criteria provided literature only

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